scholarly journals Antimicrobial Activity of Neutrophils Against Mycobacteria

2021 ◽  
Vol 12 ◽  
Author(s):  
Heather A. Parker ◽  
Lorna Forrester ◽  
Christopher D. Kaldor ◽  
Nina Dickerhof ◽  
Mark B. Hampton
Keyword(s):  
Antimicrobial Activity ◽  
Hypochlorous Acid ◽  
Mycobacterial Infection ◽  
Neutrophil Extracellular Traps ◽  
Resistance Mechanisms ◽  
Host Cells ◽  
Bacterial Clearance ◽  
Human Pathogens ◽  
Extracellular Traps ◽  
Reactive Oxidants

The mycobacterium genus contains a broad range of species, including the human pathogens M. tuberculosis and M. leprae. These bacteria are best known for their residence inside host cells. Neutrophils are frequently observed at sites of mycobacterial infection, but their role in clearance is not well understood. In this review, we discuss how neutrophils attempt to control mycobacterial infections, either through the ingestion of bacteria into intracellular phagosomes, or the release of neutrophil extracellular traps (NETs). Despite their powerful antimicrobial activity, including the production of reactive oxidants such as hypochlorous acid, neutrophils appear ineffective in killing pathogenic mycobacteria. We explore mycobacterial resistance mechanisms, and how thwarting neutrophil action exacerbates disease pathology. A better understanding of how mycobacteria protect themselves from neutrophils will aid the development of novel strategies that facilitate bacterial clearance and limit host tissue damage.

scholarly journals Inactivation of α1-proteinase inhibitor by Candida albicans aspartic proteases favors the epithelial and endothelial cell colonization in the presence of neutrophil extracellular traps.

2015 ◽  
Vol 63 (1) ◽  
Author(s):  
Mariusz Gogol ◽  
Dominika Ostrowska ◽  
Kinga Klaga ◽  
Oliwia Bochenska ◽  
Natalia Wolak ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Proteinase Inhibitor ◽  
Proteolytic Enzymes ◽  
Fungal Infections ◽  
Critical Role ◽  
Neutrophil Extracellular Traps ◽  
Host Cells ◽  
Inhibition Mechanism ◽  
Aspartic Proteases ◽  
Extracellular Traps

Candida albicans, a causative agent of opportunistic fungal infections in immunocompromised patients, uses ten secreted aspartic proteases (SAPs) to deregulate the homeostasis of the host organism on many levels. One of these deregulation mechanisms involves a SAP-dependent disturbance of the control over proteolytic enzymes of the host by a system of dedicated proteinase inhibitors, with one important example being the neutrophil elastase and alpha1-proteinase inhibitor (A1PI). In this study, we found that soluble SAPs 1-4 and the cell membrane-anchored SAP9 efficiently cleaved A1PI, with the major cleavage points located at the C-terminal part of A1PI in a close vicinity to the reactive-site loop that plays a critical role in the inhibition mechanism. Elastase is released by neutrophils to the environment during fungal infection through two major processes, a degranulation or formation of neutrophil extracellular traps (NET). Both, free and NET-embedded elastase forms, were found to be controlled by A1PI. A local acidosis, resulting from the neutrophil activity at the infection sites, favors A1PI degradation by SAPs. The deregulation of NET-connected elastase affected a NET-dependent damage of epithelial and endothelial cells, resulting in the increased susceptibility of these host cells to candidal colonization. Moreover, the SAP-catalyzed cleavage of A1PI was found to decrease its binding affinity to a proinflammatory cytokine, interleukin-8. The findings presented here suggest a novel strategy used by C. albicans for the colonization of host tissues and overcoming the host defense.

scholarly journals Leishmania donovani promastigotes evade the antimicrobial activity of neutrophil extracellular traps

2011 ◽  
Vol 5 (S1) ◽  
Author(s):  
Christelle Gabriel ◽  
Robert W McMaster ◽  
Denis Girard ◽  
Albert Descoteaux
Keyword(s):  
Antimicrobial Activity ◽  
Leishmania Donovani ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps

scholarly journals Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

2019 ◽  
Vol 119 (04) ◽  
pp. 542-552 ◽  
Author(s):  
Kristof Van Avondt ◽  
Lars Maegdefessel ◽  
Oliver Soehnlein
Keyword(s):  
Disease Risk ◽  
Neutrophil Extracellular Traps ◽  
Dnase I ◽  
Inflammasome Activation ◽  
Extracellular Traps ◽  
Thrombotic Complications ◽  
Atherothrombotic Disease ◽  
Coronary Events ◽  
Reactive Oxidants ◽  
Net Release

AbstractNeutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.

scholarly journals Tolerance to lipopolysaccharide promotes an enhanced neutrophil extracellular traps formation leading to a more efficient bacterial clearance in mice

2012 ◽  
Vol 168 (1) ◽  
pp. 153-163 ◽  
Author(s):  
V. I. Landoni ◽  
P. Chiarella ◽  
D. Martire-Greco ◽  
P. Schierloh ◽  
N. van-Rooijen ◽  
...  
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Bacterial Clearance ◽  
Extracellular Traps

scholarly journals Restoration of NET formation by gene therapy in CGD controls aspergillosis

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2619-2622 ◽  
Author(s):  
Matteo Bianchi ◽  
Abdul Hakkim ◽  
Volker Brinkmann ◽  
Ulrich Siler ◽  
Reinhard A. Seger ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Antimicrobial Activity ◽  
Nadph Oxidase ◽  
Invasive Pulmonary Aspergillosis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Neutrophil Extracellular Traps ◽  
Pulmonary Aspergillosis ◽  
Extracellular Traps ◽  
Healthy Persons

AbstractChronic granulomatous disease (CGD) patients have impaired nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function, resulting in poor antimicrobial activity of neutrophils, including the inability to generate neutrophil extracellular traps (NETs). Invasive aspergillosis is the leading cause of death in patients with CGD; it is unclear how neutrophils control Aspergillus species in healthy persons. The aim of this study was to determine whether gene therapy restores NET formation in CGD by complementation of NADPH oxidase function, and whether NETs have antimicrobial activity against Aspergillus nidulans. Here we show that reconstitution of NET formation by gene therapy in a patient with CGD restores neutrophil elimination of A nidulans conidia and hyphae and is associated with rapid cure of preexisting therapy refractory invasive pulmonary aspergillosis, underlining the role of functional NADPH oxidase in NET formation and antifungal activity.

scholarly journals Secreted Phosphatase and Deoxyribonuclease Are Required by Pseudomonas aeruginosa To Defend against Neutrophil Extracellular Traps

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Mike Wilton ◽  
Tyler W. R. Halverson ◽  
Laetitia Charron-Mazenod ◽  
Michael D. Parkins ◽  
Shawn Lewenza
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Alkaline Phosphatase ◽  
Defense Mechanism ◽  
Neutrophil Extracellular Traps ◽  
Immune Defense ◽  
Extracellular Dna ◽  
Protective Function ◽  
Content Type ◽  
Extracellular Traps

ABSTRACT Neutrophil extracellular traps (NETs) are produced by neutrophils as an innate immune defense mechanism to trap and kill microbial pathogens. NETs are comprised of ejected chromatin that forms a lattice structure enmeshed with numerous antimicrobial proteins. In addition to forming the structural backbone of NETs, extracellular DNA (eDNA) has membrane-disrupting antimicrobial activity that contributes to NET killing. Many pathogens produce secreted extracellular DNases to evade the antimicrobial activity of NETs. Pseudomonas aeruginosa encodes an operon of two secreted enzymes, a predicted alkaline phosphatase and a DNase. The DNase (eddB) degrades eDNA to use as a nutrient source. Here we report that both eDNA and NETs are potent inducers of this DNase-phosphatase operon. Furthermore, the secreted DNase contributes to degrading NET DNA and defends P. aeruginosa against NET-mediated killing. We demonstrate that EddA has both alkaline phosphatase and phosphodiesterase (PDase) activities and also protects against the antimicrobial activity of NETs. Although the phosphatase does not cause DNA degradation similar to that of the DNase, its protective function is likely a result of removing the cation-chelating phosphates from the eDNA phosphodiester backbone. Therefore, both the DNase and PDase contribute to defense against NET killing of P. aeruginosa, highlighting the role of DNA-manipulating enzymes in targeting the eDNA in neutrophil extracellular traps.

scholarly journals Histone H2A and Bovine Neutrophil Extracellular Traps Induce Damage of Besnoitia besnoiti-Infected Host Endothelial Cells but Fail to Affect Total Parasite Proliferation

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 78 ◽  
Author(s):  
Conejeros ◽  
Velásquez ◽  
Grob ◽  
Zhou ◽  
Salecker ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Host Cell ◽  
Cell Damage ◽  
Neutrophil Extracellular Traps ◽  
Host Cells ◽  
Infected Host ◽  
Parasite Development ◽  
Besnoitia Besnoiti ◽  
Extracellular Traps ◽  
Bovine Endothelial Cells

Besnoitia besnoiti tachyzoites infect and develop in bovine endothelial cells in vivo and trigger the release of neutrophil extracellular traps (NETs) from bovine polymorphonuclear neutrophils (PMN). The purpose of this study was to analyze if pure B. besnoiti tachyzoite-triggered NETs would damage endothelial host cells and subsequently influence intracellular development and proliferation of B. besnoiti tachyzoites in primary bovine endothelial cells. For comparison purposes, isolated A23187-induced NETs were also used. Thus, we here evaluated endothelial host cell damage triggered by histone 2A (H2A) and B. besnoiti tachyzoite-induced NET preparations and furthermore estimated the effects of PMN floating over B. besnoiti-infected endothelium under physiological flow conditions on endothelial host cell viability. Overall, all treatments (H2A, B. besnoiti-triggered NETs and floating PMN) induced endothelial cell death of B. besnoiti-infected host cells. However, though host cell damage led to significantly altered intracellular parasite development with respect to parasitophorous vacuole diameter and numbers, the total proliferation of the parasite over time was not significantly affected by these treatments thereby denying any direct effect of NETs on intracellular B. besnoiti replication.

Streptococcus suis DNase SsnA contributes to degradation of neutrophil extracellular traps (NETs) and evasion of NET-mediated antimicrobial activity

Microbiology ◽  
2014 ◽  
Vol 160 (2) ◽  
pp. 385-395 ◽  
Author(s):  
Nicole de Buhr ◽  
Ariane Neumann ◽  
Natalja Jerjomiceva ◽  
Maren von Köckritz-Blickwede ◽  
Christoph G. Baums
Keyword(s):  
Antimicrobial Activity ◽  
Streptococcus Suis ◽  
Neutrophil Extracellular Traps ◽  
Human Neutrophils ◽  
Myristate Acetate ◽  
Phenotypic Differences ◽  
Extracellular Traps ◽  
Partial Release ◽  
Over Time

Streptococcus suis is an important cause of different pathologies in pigs and humans, most importantly fibrinosuppurative meningitis. Tissue infected with this pathogen is substantially infiltrated with neutrophils, but the function of neutrophil extracellular traps (NETs) - a more recently discovered antimicrobial strategy of neutrophils - in host defence against Strep. suis has not been investigated. The objective of this work was to investigate the interaction of Strep. suis with NETs in vitro. Strep. suis induced NET formation in porcine neutrophils and was entrapped but not killed by those NETs. As the amount of NETs decreased over time, we hypothesized that a known extracellular DNase of Strep. suis degrades NETs. Though this nuclease was originally designated Strep. suis-secreted nuclease A (SsnA), this work demonstrated surface association in accordance with an LPXTG cell wall anchor motif and partial release into the supernatant. Confirming our hypothesis, an isogenic ssnA mutant was significantly attenuated in NET degradation and in protection against the antimicrobial activity of NETs as determined in assays with phorbol myristate acetate (PMA)-stimulated human neutrophils. Though assays with PMA-stimulated porcine neutrophils suggested that SsnA also degrades porcine NETs, phenotypic differences between wt and the isogenic ssnA mutant were less distinct. As SsnA expression was crucial for neither growth in vitro nor for survival in porcine or human blood, the results indicated that SsnA is the first specific NET evasion factor to be identified in Strep. suis.

scholarly journals β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps

2014 ◽  
Vol 211 (7) ◽  
pp. 1485-1497 ◽  
Author(s):  
Martin J. Raftery ◽  
Pritesh Lalwani ◽  
Ellen Krautkrӓmer ◽  
Thorsten Peters ◽  
Karin Scharffetter-Kochanek ◽  
...  
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Lung Damage ◽  
Hantavirus Infection ◽  
Human Pathogens ◽  
Integrin Receptors ◽  
Β2 Integrin ◽  
Extracellular Traps ◽  
Nuclear Antigens ◽  
Complement Receptor 3 ◽  
Underlying Mechanisms

Rodent-borne hantaviruses are emerging human pathogens that cause severe human disease. The underlying mechanisms are not well understood, as hantaviruses replicate in endothelial and epithelial cells without causing any cytopathic effect. We demonstrate that hantaviruses strongly stimulated neutrophils to release neutrophil extracellular traps (NETs). Hantavirus infection induced high systemic levels of circulating NETs in patients and this systemic NET overflow was accompanied by production of autoantibodies to nuclear antigens. Analysis of the responsible mechanism using neutrophils from β2 null mice identified β2 integrin receptors as a master switch for NET induction. Further experiments suggested that β2 integrin receptors such as complement receptor 3 (CR3) and 4 (CR4) may act as novel hantavirus entry receptors. Using adenoviruses, we confirmed that viral interaction with β2 integrin induced strong NET formation. Collectively, β2 integrin–mediated systemic NET overflow is a novel viral mechanism of immunopathology that may be responsible for characteristic aspects of hantavirus-associated disease such as kidney and lung damage.

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